Bone is a common site of metastasis for breast cancer. Although rarely "cured" of breast cancer, patients with bone-dominant breast cancer have a more favorable prognosis than patients with visceral involvement and may have prolonged survival. These patients benefit from an increasing array of effective therapies;however, the choice of therapy is hampered by the difficulty of assessing response. We have shown, in retrospective studies, that serial FDG PET can measure bone metastasis response to therapy, that changes in FDG uptake with treatment predict time-to-progression (TTP), and that the level of FDG uptake predicts the likelihood of skeletal-related events (SRE), such as fracture. We have also used 18F-fluoride PET to assess tumor effect on the1 bone adjacent to metastases and have shown that the information gained on bone metastasis behavior from fluoride PET is distinct from and complementary to FDG PET. We now propose to extend these preliminary studies to a larger prospective study of FDG and fluoride PET in patients with bone-dominant breast cancer undergoing systemic therapy. Our aims are (1) to prospectively validate FDG and fluoride PET as measures of bone metastasis response to therapy with patient outcome as the gold standard, (2) to measure the in vivo biology of metastatic sites and adjacent bone using a combination of quantitative FDG PET/CT and fluoride PET with the goal of predicting the risk of a skeletal event and also to relate PET measures to tumor characteristics measured by in vitro assay of biopsy material, and (3) to measure the early effect of bisphosphonates on bone turnover using fluoride PET to better understand the in vivo effect of these agents, which are almost universally used in treating breast cancer metastases. The result of these investigations will be imaging methods, validated by patient outcome, for measuring breast cancer bone metastasis response in clinical trials and clinical practice and for directing appropriate early interventions to prevent skeletal events.